But not in most adult hepatocytes. Intrahepatic Cholangiocarcinoma The origin of intrahepatic cholangiocarcinoma is much less defined when compared with HCC. However, since that incidence and mortality of ICCs clarifying AZD1480 the origin of these tumors is im portant. Recent studies suggest that some ICCs could arise from liver stem cells rather than from mature cholangiocytes. This concept is supported by the identification of a combined hepatocellular cholangi ocarcinoma, which have morphological and phenotypical intermediate features between HCC and ICC. The ability of HPCs to differentiate towards the biliary and the hepatocytic lineages gave rise to the hypothesis that transformed HPCs are the source of origin of intermediate primary liver carcinomas.
Some BMS-536924 animal models reveal that ICC can originate from HPCs. Furthermore, in a few cases of human ICCs, it has been reported that some tumor cells express specific markers of liver stem cells, indi cating a possible stem cell origin. However, there is currently not enough data to make a state ment regarding a stem cell origin of ICC and further immunohistochemical characteristics related to the expression of hepatic stem cell markers in ICCs should be elucidated. Molecular signaling of Liver Cancer Stem Cells Wnt ??catenin signaling pathway The Wnt ??catenin pathway is an evolutionarily well conserved pathway to be essential to normal cellular processes such as development, growth, sur vival, regeneration, and self renewal.
Disruption of Wnt ??catenin signaling results from both genetic and epigenetic changes is associated with a range of diseases and is frequently found in many cancers, especially colon cancer and HCC. Disrupted Wnt ??catenin signaling by mutational and non mutational events is observed in about one third of all HCCs which emphasizes the importance of this pathway in hepatocarcinogenesis. The Wnt pathway diversifies into two main branches, i.e, ca nonical and non canonical, which play critical roles in specifying cellular fates and movements, respectively, during both embriogenic development and adult tis sue regeneration. Wnt ligands signal through binding to seven transmembrane Frizzled receptors and single transmembrane lipoprotein receptor related protein 5 or 6 co receptors.
Canonical signaling mediated by ligands such as Wnt3a inhibits a multi protein degradation complex consisting minimally of axin, adenomatous polyposis coli and glycogen synthase kinase 3??. This inhibition culminates in nuclear translocation of ??catenin, ena bling it to interact with T cell factor lymphoid enhancer factor transcription factors to regulate gene expression. Non canonical signaling, which is much less de fined, is mediated by ligands such as Wnt11 that uses the same Fzd receptors. The Wnt Fzd complex interacts with heterotrimeric G and Dv1 proteins to activate phospholipase C, which then generates di acylglycerol and inositol phosphatase from phospha tidyl inositol 4, 5 biphosp